He was a member of the writing panel and an executive producer/co-showrunner on the dramedy series Ugly Betty, initially having been a co-executive producer. Ugly Betty's creator and other showrunner Silvio Horta was named AfterElton.com's Man of the Year for 2007 for the show's positive portrayal of LGBT issues—including a possibly gay teenager, a transgender man-turned-woman and a gay male assistant with a homophobic mother—and had to say about Pennette, also gay: "Marco Pennette, my co-showrunner and Executive Producer, deserves a special thanks here too. He is an MVP of comedy, and a big part of Ugly Betty's gay sensibility."[11] On February 11, 2008, ABC picked up Ugly Betty for the 2008-09 television season, but on the day the renewal was announced, Pennette, along with fellow executive producer James Hayman, were let go. The departures of Pennette and Hayman added to the constant turnovers on the series off-camera, which has so far seen five writers having exited or been fired.[12]

Openly gay, Pennette was outed by a colleague network executive on the People's Choice Awards red carpet when asked about his boyfriend in front of his family members, who were unaware of his sexuality.[14] His long-time partner is television talent manager Steve Rabiner,[15] with whom he has three daughters, Ally[14] Chelsea,[4] and Zoe, all born by surrogate pregnancy, the inspiration for his medical drama Inconceivable.[5][7] His own family experiences were the basis for his sitcom Crumbs; his brother's drowning, his mother's institutionalization and his father's impregnation of another woman.[14][16]

He is a good friend of Broadway theatre spokesman Seth Rudetsky, having hired him previously to write a song for a character in his sitcom Caroline in the City—an IRS employee auditioning for the musical Cats.[17]